Device and Method for Treating Cardiac Disorders by Modulating Autonomic Response

ABSTRACT

A method and device for modulating the autonomic nervous system adjacent a pericardial space to treat cardiac arrhythmia includes a treatment source arranged to supply a treatment medium, a catheter having an end sized for insertion into the pericardial space, a medium delivery assembly having a distal end arranged to be positioned by the catheter into the pericardium, with the distal end of the delivery assembly comprising a delivery tip arranged to extend away from the distal end of the catheter into the pericardial space. A connector operatively couples the delivery tip of the medium delivery assembly to the treatment source, and the delivery tip of the medium delivery assembly including a plurality of delivery points for delivering the treatment medium at a plurality of treatment areas within the pericardial space. The device performs modulation or ablation of the autonomic nervous system at selected treatment areas within the pericardium.

FIELD OF THE INVENTION

The present invention relates generally to the treatment of cardiacdisorders by recognizing, approximating and/or locating autonomicstructures in or around the heart, such as on the surface of the heartor within the pericardial space, and treating or manipulating theseautonomic structures with, for example, one or more of stimulation,blocking, ablation, or denervation.

BACKGROUND

The heart is surrounded by an autonomic nervous system (ANS) network. Itis well accepted that the autonomic nervous system network createsautonomic responses in the heart. Generally speaking, a variety ofnervous tissues such as nerves, ganglia, etc., are disposed on thesurface of the heart, in the epicardium or myocardium of the heart, onthe pericardial sac surrounding the heart sac, within, upon or beneaththe pericardial sac.

This network of nervous tissue includes a variety of nerves and tissue,including the neurons, axons, dendrites, plexi, ganglia and gangliabundles. In neurological contexts ganglia/ganglion are composed mainlyof somata and dendritic structures which are bundled or connectedtogether. Ganglia often interconnect with other ganglia to form acomplex system of ganglia known as a plexus. Ganglia provide relaypoints and intermediary connections between different neurologicalstructures in the body, such as the peripheral and central nervoussystems.

Autonomic ganglia, which may be referred to as part of the autonomicnervous system, are those ganglia that contain the cell bodies ofautonomic nerves. The autonomic nervous system (ANS or visceral nervoussystem) is the part of the peripheral nervous system that acts as acontrol system functioning largely below the level of consciousness, andcontrols visceral functions. The ANS affects, for example, heart rate,digestion, respiration rate, salivation, perspiration, the diameter ofthe pupils, micturition (urination), and sexual arousal. Whereas most ofthe actions of the ANS are involuntary, some actions, such as breathing,work in tandem with the conscious mind. The ANS is classically dividedinto three subsystems: the enteric nervous system, the parasympatheticnervous system and the sympathetic nervous system. Relatively recently,an important subsystem of autonomic neurones that have been named‘non-adrenergic and non-cholinergic’ neurones (because they use nitricoxide as a neurotransmitter) have been described and found to beintegral in autonomic function, particularly in the gut and the lungs.With regard to function, the ANS is usually divided into sensory(afferent) and motor (efferent) subsystems. Within these systems,however, there are inhibitory and excitatory synapses between neurones.

Other forms of ganglia include cardiac ganglia. Exemplary forms ofcardiac ganglia include, for example, retro-atrial ganglion,interarterial ganglia, aortocaval ganglia, and ganglia around theOblique Sinus of the heart. These latter ganglion include, for example,the left superior ganglia, the left inferior ganglia, the right superiorganglia, and the right inferior ganglia. There are additional gangliaaround the Transverse Sinus of the heart.

Those of skill in the art will realize that still other neural andganglia structures exist. A more complete discussion of gangliastructures and their topography can be found in Topography of CardiacGanglia in the adult Human Heart.

SUMMARY

In accordance with one aspect of the invention, a method of modulatingthe autonomic nervous system adjacent a pericardial space to treatcardiac disorders comprises the steps of providing a source of atreatment medium, the treatment medium effective to, for example,modulate and/or ablate autonomic nervous system activity, providing anapparatus, for example a catheter, having a proximal end and a distalend, the distal end sized for insertion into the pericardial space at anentry point, providing a delivery assembly for delivery of the treatmentmedium, the delivery assembly having a proximal end and a distal end,the distal end arranged to be positioned by the distal end of thecatheter, providing the distal end of the delivery assembly with adelivery tip, which may include a mapping array, the delivery tipoperatively coupled to the source, the delivery tip or the deliveryassembly arranged to position the delivery assembly or tip and toperform a modulation step to deliver the treatment medium to a selectedlocation, and/or the mapping array may be arranged to sense a level ofautonomic nervous system activity within the pericardial space and tocreate an output, using the output to position the delivery tip at aselected treatment location within the pericardial space, and performinga modulation step by supplying the treatment medium to the selectedlocation via the delivery tip.

In accordance with one or more preferred forms, the method may includeproviding the delivery tip of the medium delivery assembly with aplurality of delivery points, and using the plurality of delivery pointsto disperse the treatment medium at a plurality of treatment areaswithin the pericardial space. Further, delivery tip of the mediumdelivery may be provided with a dispersion means having an exposed area,which may be used to disperse the treatment medium over a treatmentarea, the treatment area greater than the exposed area. Additionalpreferred steps may include using the mapping array after the modulationstep to sense a follow-up level of autonomic nervous system activity atthe selected location, and comparing the follow-up level of autonomicnervous system activity to a threshold. One may determine, directly orindirectly, whether the follow-up level of autonomic nervous systemactivity is above a threshold, and then perform a subsequent modulationstep.

The preferred method may include providing a monitor arranged to createan output, periodically using the mapping array after the modulationstep to sense a follow-up level of autonomic nervous system activity atthe selected location and providing a subsequent output to the monitor,comparing the subsequent output to the threshold level of autonomicnervous system activity, and determining whether an additionalmodulation step is desired. It is also contemplated to use the mappingarray or other suitable mapping means after the modulation step to sensea follow-up level of autonomic nervous system activity at the selectedlocation and provide a subsequent output to the monitor, compare thesubsequent output to the threshold level of autonomic nervous systemactivity, determining whether an ablation step is desired, and performthe ablation step by supplying the treatment medium to the selectedlocation via the delivery tip. The method contemplates determining anamount of the treatment medium effective to perform the modulationand/or ablation step, determining a desired duration for the modulationstep, and performing the modulation step for the desired duration. Themapping means or mapping array may be operatively coupled to an externalsystem such as, for example, an ECG system, to determine effectiveness.

In accordance with an exemplary aspect, the system may use dynamicmodulation with on-line monitoring for autonomic effects. This includesa specific algorithm involving pacing from one or more poles of thearray or separate catheters at high and low rate timed so as not tocapture atrial myocardium. Analysis of the retrieved signals comparedprior to and after intervention will allow detection of whether thedesired result on autonomic modulation has been achieved. Specifically,it will be possible to monitor one or more of changes in blood pressure,heart rate, atrioventricular nodal conduction, atrial myocardialrefractory period, and heart rate variation along with the frequency andoccurrence of the specific detected electrograms in and around thecardiac ganglia.

In accordance with further preferred aspects, the method includes usingthe mapping array after the modulation step to sense a follow-up levelof autonomic nervous system activity at the selected location, comparingthe follow-up level of autonomic nervous system activity to a threshold,and performing a subsequent permanent modulation step. Additionalpreferred steps include providing the delivery tip with an expandableportion shiftable between a collapsed state and an expanded state,coupling the delivery tip to the expandable portion, and expanding theexpandable portion after placement of the delivery tip at the locationwithin the pericardial space. Further steps include selecting thetreatment medium as one of electrical energy, a pharmaceuticalcomposition, a chemical composition, an exothermic agent, an endothermicagent, or vibration.

In accordance with a yet further aspect of the invention, a method ofmodulating the autonomic nervous system adjacent a pericardial space totreat cardiac disorders comprises the steps of providing a catheterhaving a proximal end and a distal end, the distal end sized forinsertion into the pericardial space, providing a delivery assembly, thedelivery assembly having a proximal end and a distal end, the distal endarranged to be positioned by the distal end of the catheter, providingthe distal end of the delivery assembly with a delivery tip, andproviding the delivery tip with an electrode array, positioning to thecatheter to place the delivery tip at a location in the pericardialspace, using the electrode array to take a first indication of autonomicnervous system activity at the location, using the electrode array toapply electrical energy at the location, using the electrode array totake a second indication of autonomic nervous system activity at thelocation, and comparing the first indication and the second indicationto determine whether the autonomic nervous system activity has beenmodulated at the location. The electrical energy may take one of anumber of possible forms.

In accordance with additional preferred forms, the method may includeproviding the delivery tip with an expandable portion shiftable betweena collapsed state and an expanded state, positioning the electrode arrayon or within the expandable portion, expanding the expandable portionafter placement of the delivery tip at the location within thepericardial space. Further, the method may include forming theexpandable portion from an expandable metal material, securing theexpandable portion in the collapsed state using a sheath, and shiftingthe expandable portion to the deployed state by removing the sheathafter placing the expandable portion at the location. An expansionballoon may be coupled to an expansion medium, and the balloon may beshifted to the deployed state by communicating the expansion medium tothe balloon after placing the balloon at the location. Further, anexpandable porous medium may be coupled to an expansion delivery meansand the medium may be shifted to the expanded state by communicating theexpansion agent or energy to the medium after placing the active area atthe location and urging the treatment means into close contact with thearea to be treated.

Further preferred steps include providing a processor operable toexecute a filtering algorithm, providing an electrical coupling betweenthe electrode array and the processor, communicating the firstindication to the processor as a first input and the second indicationto the processor as a second input, using the filtering algorithm togenerate to an output indicative of the first indication or the secondindication, and comparing the output to a threshold level of autonomicnervous system activity.

In accordance with yet another aspect of the invention, a method formodulating the autonomic nervous system adjacent a pericardial space totreat cardiac disorders comprises the steps of providing a catheterhaving a proximal end, and a distal end, the distal end sized forinsertion into the pericardial space, providing a treatment sourcearranged to supply a treatment medium, providing a medium deliveryassembly, the medium delivery assembly having a proximal end and adistal end and sized to extend through the lumen of the catheter,providing the distal end of the delivery assembly with a delivery tiparranged to extend from the distal end of the catheter and into thepericardial space, providing the delivery tip with a plurality ofelectrodes, providing a connector operatively coupling the delivery tipof the medium delivery assembly to the treatment source, and providingthe delivery tip of the medium delivery assembly with a plurality ofdelivery points for delivering the treatment medium at a plurality oftreatment areas within the pericardial space.

In accordance with yet an additional aspect of the invention, a methodfor modulating the autonomic nervous system adjacent a pericardial spaceto treat cardiac disorders comprises providing a catheter having aproximal end, and a distal end, the distal end sized for insertion intothe pericardial space, providing a source of electrical energy,providing a delivery assembly, the medium delivery assembly having aproximal end and a distal end, the distal end arranged to be positionedby the distal end of the catheter, providing the distal end of thedelivery assembly with a delivery tip comprising a plurality ofelectrodes sized for placement in the pericardial space, the pluralityof electrodes operatively coupled to the source and forming a pluralityof delivery points for delivering the electrical energy from the sourceto a plurality of treatment areas within the pericardial space,selecting a treatment location within the pericardial space, performinga modulation step by applying electrical energy form the source to thetreatment location via the delivery tip.

In accordance with a further exemplary aspect, the system may include adevice that allows pericardial manipulation without “leakage” ofinstilled material into the extra pericardial space. Specifically, twocontaining components are created, which may take the form of phalangesor wings on the sheath placed into the pericardial space, and thesecomponents may be formed of a finely enmeshed Nitinol. The componentsexpand on either side of the pericardium at the site of entry. These canthen be manually approximated so as to create as new. This iteration ofthe sheath may be particularly compatible with modulation optionsdescribed below where direct current energy is accomplished via avirtual electrode created by instilled pericardial saline and forinstallation of alcohol or other ganliolytic agents.

In accordance with another aspect, a method for modulating the autonomicnervous system adjacent a pericardial space to treat cardiac disorderscomprises providing a catheter having a proximal end and a distal end,the distal end sized for insertion into the pericardial space, providinga delivery assembly, the medium delivery assembly having a proximal endand a distal end, the distal end arranged to be positioned by the distalend of the catheter, providing the distal end of the delivery assemblywith a delivery tip sized for placement in the pericardial space, thedelivery tip comprising a movable component arranged to apply energy,for example kinetic, mechanical or other suitable energy, to a treatmentlocation within the pericardial space adjacent the delivery tip,providing a mapping array comprising a plurality of electrodespositionable within the pericardial space, the mapping array to sense alevel of autonomic nervous system activity within the pericardial spaceand to create an output, using the output to position the delivery tipat the treatment location within the pericardial space, performing amodulation step by activating the movable component.

In further accordance with one or more of the exemplary forms discussedherein, exemplary methods of treating may include performingmodulations/interventions of varying durations. By varying the duration,it is possible to achieve varying effects on the targeted treatmentarea. For example, the effect of a modulation may be temporary and/orreversible, or the effect of a modulation step may be irreversible inthe form of a permanent ablation or inactivation of the targeted nervoustissue. Additionally, variations in duration may be selected based onwhether the condition is acute, sub-acute, or chronic. For example, fortreatment of an acute condition, the method may consist of modulationover a relatively short term measured in, for example, minutes or hours.Once again, this modulation may be performed electrically, mechanically,chemically, or using thermal approaches. For treatment of a sub-acutecondition, the treatment may be performed over an intermediate termwhich may be measured, for example in days. One exemplary treatment forsub-acute conditions may involve the placement of a fluid retentionelement filled with, or in flow communication with, a treatment sourceconsisting of, for example, alcohol, procainamide, beta blockers, orother suitable agents. These agents may be placed in the pericardialspace for a period of days, and using the sensing functions discussedherein, or other suitable sensing functions, the level of autonomicnervous system activity may be periodically assessed over a selectedtime frame. During the ensuing time period, adjustment of the modulationstep or permanent ablation may be performed. In the face of chronicconditions, the treatment may be performed over a relatively long timewhich may be measured, for example, in weeks, months or years oftreatment. Treatment of chronic conditions may include placingimplantable devices to deliver treatment in the form of electricalenergy, mechanical cutting or vibration, chemical agents, or thermaltherapy. These exemplary therapies can be delivered continuously, or thedevice can reside in place and can receive inputs from a sensingcomponent that monitors the heart to detect a disorder that requirestherapy. The system can then deliver therapy when additional therapy isdesired.

In further accordance with one or more of the exemplary methodsdiscussed herein, treatment may be implemented or selected to havevarying effects on the autonomic nervous system. The disclosed systemand methods may modulate the targeted treatment area without permanentlyaffecting that target, such as by electrical stimulation or blocking ofautonomic nerve signals, without damaging the nerve. Alternatively, atargeted area may be permanently modulated by, for example, thermal,chemical, electrical, or mechanical ablation/destruction of a nerve organglia.

Using the exemplary system and methods described herein, treatment of anumber of cardiac disorders, as well as autonomic disorders related tocardiac function, can be treated by modulating autonomic response. Forexample, the disclosed system and method may be used to treat cardiacarrhythmias such as atrial fibrillation, ventricular fibrillation,atrial or supra-ventricular ventricular tachycardias, neurocardiogenicsyncope, inappropriate sinus tachycardia, and postural orthostatictachycardia syndrome. Additional conditions that can be treated includeforms of heart failure such as, for example, diastolic dysfunction andcardiomyopathy, as well as one or more sources of pain such as cardiacand non-cardiac related chest pain.

It may be desirable to target these autonomic responses via ANSmodulation as a means or method of treating a variety of cardiacdisorders, such as, for example, cardiac arrythmias. In general, in atleast some forms of treatment it may be desirable to modulate theautonomic nervous system, and to do so without causing damage to othertissues of the heart, such as the myocardium and/or surrounding tissuesand blood vessels. As disclosed herein, modulating the target meansaffecting the normal/natural function of the targeted area in a way thatchanges the physiology or physiologic activity of the system. The meansof modulation includes electrical, chemical, thermal, or mechanicalmodulation and/or ablation. In electrical modulation, electrical energyis sent or otherwise applied to the targeted are of the ANS and sends ordisrupts signals along the ANS tissue. Using direct current (DC) oralternating current (AC), one may temporarily or permanently disruptsignals along the nervous tissue.

Mechanical means may include vibrational energy to send of disruptsignals along nervous tissue, or physically severing or otherwisedisrupting nervous tissue, while chemical means may include the use ofagents that destroy nervous tissue to disrupt signals along nervoustissue (e.g. ethanol, phenol, etc), or use of drugs that temporarilydisrupt signals along nervous tissue (e.g. procainamide, lidocaine), oragents to induce signals along nervous tissue. Finally, thermal mayinclude the use of Radio Frequency energy to temporarily or permanentlydisrupt signals along nervous tissue, or use of cryogenic energy(cooling) to temporarily or permanently disrupt signals along nervoustissue.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 schematic view of a device for modulating the autonomic nervoussystem adjacent a pericardial space to treat cardiac arrhythmia and/orother cardiac disorders and assembled in accordance with the teachingsof a disclosed example of the present invention.

FIG. 2 is an enlarged fragmentary elevational view of one exemplary formof an expandable treatment delivery tip forming the treatment deliveryassembly portion of the device of FIG. 1 and shown in a collapsed orundeployed state.

FIG. 3 is another enlarged fragmentary view of the treatment deliverytip of FIG. 2 showing the treatment delivery tip in an expanded ordeployed state.

FIG. 4 is an enlarged fragmentary elevational view of another exemplaryform of an expandable treatment delivery tip shown in a collapsed orundeployed state.

FIG. 5 is another enlarged fragmentary view of the treatment deliverytip of FIG. 5 showing the treatment delivery tip in an expanded ordeployed state.

FIG. 6 is an enlarged fragmentary elevational view of still anotherexemplary form of an expandable treatment delivery tip shown in acollapsed or undeployed state.

FIG. 7 is another enlarged fragmentary elevational view of the treatmentdelivery tip of FIG. 6 showing the treatment delivery tip in an expandedor deployed state.

FIG. 8 is an enlarged fragmentary plan view of the treatment deliverytip of FIGS. 6 and 7 showing the treatment delivery tip in an expandedor deployed state from a different perspective.

FIG. 9 is an enlarged fragmentary elevational view of still anotherexemplary form of an expandable treatment delivery tip having anelectrode array and shown in an expanded or deployed state.

FIG. 10 is an enlarged fragmentary elevational view of yet a furtherexemplary form of an expandable treatment delivery tip having anexpandable electrode array and shown in an expanded or deployed state.

FIG. 11 is an enlarged fragmentary cross-sectional view of a heartillustrating the treatment delivery tip of FIGS. 2 and 3 inserted intothe pericardial space between the pericardium and the myocardium at afirst location, and further illustrating the treatment delivery tip ofFIGS. 6-8 inserted into the current pericardial space at a secondlocation.

FIG. 12 is an enlarged cross-sectional view of a heart illustratingvarious ganglionic areas of interest and the delivery of a catheter tovarious locations along the heart.

FIG. 13 is another enlarged fragmentary cross-sectional view of a heartillustrating a treatment delivery assembly having infusion ports,suction ports, and a blocking agent disposed in the selected treatmentarea and coupled to a control unit for the treatment medium comprising apump and a reservoir.

FIG. 14 is yet another enlarged fragmentary cross-sectional view of aheart illustrating another exemplary treatment delivery tip having anelectrode array and an infusion system encircling a ventricle of theheart within the pericardial space.

FIG. 15 is an enlarged fragmentary plan view illustrating an exemplarytreatment delivery tip having an electrode array and a cryogenicelement.

FIG. 16 is another enlarged fragmentary plan view illustrating theexemplary treatment delivery tip having an electrode array and acryogenic element mounted on an expandable component.

FIG. 17 is another view of the delivery tip of FIG. 16 illustratingthermal insulation applied to the delivery tip.

FIG. 18 is another enlarged fragmentary plan view illustrating anotherexemplary treatment delivery tip having an electrode array, an elongatecryogenic element, and an insulative coating.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Although the following text sets forth a detailed description of anexemplary embodiment of the invention, it should be understood that thelegal scope of the invention is defined by the words of the claims setforth at the end of this patent. The detailed description is to beconstrued as exemplary only and does not describe every possibleembodiment of the invention since describing every possible embodimentwould be impractical, if not impossible. Based upon reading thisdisclosure, those of skill in the act may be able to implement one ormore alternative embodiments, using either current technology ortechnology developed after the filing date of this patent. Suchadditional indictments would still fall within the scope of the claimsdefining the invention.

Referring now to the drawings FIG. 1 illustrates a device 10 formodulating the autonomic nervous system assembled in accordance with theteachings of a disclosed example of the present invention. The device 10includes a treatment source 12 arranged to supply a treatment medium 14.The treatment medium 14 as illustrated only schematically in FIG. 1, andcertain exemplary forms for the treatment medium 14 will be discussed ingreater detail below. A catheter 16 is shown and includes a proximal end18 and a distal end 20, with the distal end 20 sized for insertion intoa pericardial space. A variety of conventional catheters available mayprove suitable. The pericardial space is not shown in FIG. 1, but willbe discussed in greater detail below. The device 10 also includes amedium delivery assembly 22 having a proximal end 24 and a distal end26. The proximal end 24 of the medium delivery assembly 22 may protrudefrom the proximal end 18 of the catheter 16. Alternatively, the proximalend 24 of the medium delivery assembly 22 may be concealed within thecatheter 16 and accessible via, for example, a suitable access port 28.Those of skill in the art will appreciate that the catheter 16 may beused to position the distal end 20 of the catheter a selected locationwithin the pericardial space, such that the distal end 26 of the mediumdelivery assembly 22 may be positioned and the desired location withinthe pericardial space by the catheter 16. The distal end 26 of thedelivery assembly 22 includes a delivery tip 30 arranged to extend awayfrom the distal end 20 of the catheter 16 into, for example, thepericardial space. The delivery tip 30 may take a number of possibleforms as will be outlined in greater detail below, and in one or moreexemplary forms the delivery tip 30 may include an expandable portion aswell as some means or mechanism for dispersing the treatment medium overan area larger than the area of the delivery tip itself, which will beoutlined in greater detail below. A connector 32 is provided whichoperatively couples the delivery tip 30 of the medium delivery assembly22 to the treatment source 12 and hence to the treatment medium 14.Although only a portion of the connector 32 as shown in FIG. 1, it willbe understood that the connector 32 may run through a lumen L of thecatheter 16 or, alternatively, may run along the catheter 16. Stillfurther alternatives are possible.

As used herein, it is contemplated that the delivery tip may take anumber of possible forms. For example, a portion of the delivery tip mayform an anchoring portion, or a separate anchoring component may beemployed. For example, the delivery tip may have a curve or bend, andthe portion of the delivery tip that delivers the treatment medium maybe carried on an inside curve, a lateral curve, or and outside curve ofa bend, and the device may use a reversible or irreversible anchor tourge the delivery tip/treatment means against the target or desiredarea. This may be especially useful in, for example, the oblique sinus.Those of skill in the art, upon reading the present disclosure, willunderstand that the use of the term “delivery tip” herein would includesuch situations where the delivery tip includes or is used inconjunction with a separate anchor, and would include situations wherethe actual treatment delivery means or mechanism is not disposed at thedistal-most portion of the delivery assembly.

Depending on the specific form of the treatment medium 14, the connector32 may take a variety of forms as will be discussed in greater detailbelow. Consequently, the delivery tip 30 is capable of routing orcommunicating the treatment medium 14 into the pericardial space in anumber of possible manners, with specific exemplary manners to bediscussed in greater detail below. The delivery tip 30 of the mediumdelivery assembly 22 includes a plurality of delivery points fordelivering the treatment medium at a treatment area or at a plurality oftreatment areas within the pericardial space.

Referring still to FIG. 1, in one or more preferred forms, the device 10may include an electrode system or array 34. The electrode array 34 maytake the form of one or more individual electrodes 35. The electrodes 35may be, for example, either a single or a plurality of unipolarelectrodes with a common return electrode, or may be a single orplurality of bipolar pairs of electrodes which may be contiguous ornon-contiguous. The electrode array is shown only schematically inFIG. 1. The electrode array 34 is preferably coupled to a signalmonitoring and control system 36 by a suitable link 38 which may extendthrough the catheter 16, or which alternatively may extend along thecatheter 16, or which further may be routed to the desired pericardialspace using other conventional means. The signal monitoring and controlsystem 36 preferably is coupled to a processor 40, and the processor 40may include a memory which may store a filtering algorithm as a set ofinstructions in a computer readable medium. As will be explained ingreater detail below, the electrode array 34 may be used to sense thelevel of autonomic nervous system activity within the pericardial spaceand, either alone or in combination with the signal monitoring andcontrol system 36, will generate an output indicative of the level ofautonomic nervous system activity sensed by the electrode array 34.Preferably, the electrode array 34, the electrode 35, and the signalmonitoring and control system 36 together form a navigation or mappingsystem 37 to aid the operator in identifying a desired or targettreatment area, and in delivering treatment.

Referring now to FIGS. 2 and 3 of the drawings, an exemplary form of adelivery tip 130 is shown and is assembled in accordance with theteachings of a first disclosed example of the present invention. Thedelivery tip 130 is attached to or otherwise forms the distal end 26 ofthe delivery assembly 22 and is shown protruding from the distal end 20of the catheter 16. The delivery tip 130 includes an expandable end 132which is shiftable between a collapsed state as shown in FIG. 2 and anexpanded state as shown in FIG. 3. A sheath 134 may be provided as shownin FIG. 2 in order to constrain the expandable end 132 in the collapsedstate. As shown in FIG. 3, the expandable end 132 may be formed from anumber of possible structures including, for example, an expandableballoon, an expandable metal material such as NITINOL, or an expandableporous medium, such as foam. Still further structures may provesuitable. Preferably, the electrode array 34 is carried on theexpandable end 132, with the electrode array 34 including a number ofindividual electrodes 35, all of which are connected to the link 38. Theexpandable end 132 may also include a fluid retention element 136 suchas, for example, a fabric material, a foam, a sponge. Other fluidretention elements may prove suitable. The expandable end 132 isconnected to a suitable conduit which in turn is connected to or forms apart of the connector 32 discussed above with respect to FIG. 1.Consequently, by routing the treatment medium 14 from the source 12 intothe expandable end 132, the expandable end 132 may be expanded to theexpanded or deployed state of FIG. 3. Upon delivery, the expandable end132 may expand into a given space such as, for example, the pericardialsac, the transverse sinus, the oblique sinus, etc. In accordance withthe example disclosed in FIGS. 2 and 3, the electrode array 35 mountedon the expandable element 132 can be used as part of the mapping system37 for mapping (i.e., to navigate to the desired treatment site, and todetermine the orientation of the expandable end 132 at or adjacent tothe treatment site). In further accordance with the example disclosed inFIGS. 2 and 3, the electrode array 35 may be used to deliver thetreatment medium 14 in the form of energy to a selected treatment site.When energy is selected as the treatment medium 14, the energy may takea variety of forms such as, for example, radiofrequency (RF) energy,direct current (DC) energy, or pulsed electric fields (PEF).Consequently, by delivering energy in any one of the chosen forms, it ispossible to modulate nerve signals, such as by blocking nervous systemactivity, stunning the nervous system activity, or permanently ablatingthe nervous system activity. In the example of FIG. 3, when a chemicalor pharmaceutical agent is selected as the treatment medium 14, theexpandable end 132 may be connected via the connector 32 to thetreatment source 12 in order to form an infusion system 134 to deliverchemical agents (drugs, alcohol, etc) to the expandable end 132 andhence into the cardiac space. As an alternative, the expandable end 132may contain or be covered with the fluid retention element 136 to holdthe selected treatment medium in a confined area to prevent damage tosurrounding tissues. In cross-section, the expandable end 132 may berelatively flat to allow for deployment and positioning in thepericardial space.

Referring now to FIGS. 4 and 5, another exemplary form of a delivery tip230 is shown and is assembled in accordance with the teachings of asecond disclosed example of the present invention. The delivery tip 230again is attached to or otherwise forms the distal end 26 of thedelivery assembly 22 and is shown protruding from the distal end 20 ofthe catheter 16. In the example of FIGS. 4 and 5, the expandable end 232forms a design for facilitating directional deployment of the selectedtreatment medium 14. Preferably, the electrode array 35 is carried onthe expandable end 232, with the electrode array 35 including a numberof individual electrodes, all of which are connected to the link 38. Aswith the example of FIG. 3, when a chemical or pharmaceutical agent isselected as the treatment medium 14, the expandable end 232 may beconnected via the connector 32 to the treatment source 12 in order toform an infusion system 234 including a plurality of spaced infusionports 236 which may function to deliver chemical agents (drugs, alcohol,etc.) to the expandable end 232 and hence into the cardiac space. Theexpandable end 232 may be expanded in a manner similar to that discussedabove with respect to FIGS. 2 and 3, and may, like all the exemplarydelivery tips outlined herein, use a sheath to maintain the expandableend in the collapsed state during delivery.

The shaft of the catheter 16 may include or contain differentialcoatings 235 such as, for example, echogenic coatings, radiopaquecoatings, or other coatings, to allow the operator to visualize theorientation of the catheter/delivery tip 230 once it is in positionwithin the desired cardiac space. All other delivery tips outlinedherein may also use such coatings as a navigation and deployment aid.The expandable end 232 again preferably includes the electrodes 35,which may be mounted on any surface of the expandable end 232. As withany of the electrodes discussed herein, the electrodes preferably arelabeled to allow the operator to know which electrodes are on which sideof the expandable element, which serves to facilitate orientation of thedevice during delivery. Alternatively, the electrodes may be disposed ononly a single surface of the delivery tip 230 to allow for differentialmapping of tissue to allow for orientation. In accordance with thedisclosed example, the ports 236 of the infusion system 234 may bepositioned and/or oriented to have directional capabilities, and thusmay deliver the treatment medium 14 in line with the orientation of theelectrodes/catheter coatings. Further, the expandable end 232 maycontain or be covered with a fluid retention element of the typediscussed above with respect to FIGS. 2 and 3, and also may contain orbe covered by a polymer cover 237 in an orientation which would containor otherwise prevent the treatment medium 14 being delivered fromleaking back towards surrounding tissues.

Referring now to FIGS. 6-8, a still further exemplary form of a deliverytip 330 is shown and is assembled in accordance with the teachings of asecond disclosed example of the present invention. The delivery tip 330again is attached to or otherwise forms the distal end 26 of thedelivery assembly 22 and is shown protruding from the distal end 20 ofthe catheter 16. In the example of FIG. 6, the distal end 26 of thedelivery assembly forms a conduit for directing the treatment medium 14in the form of a fluid into the pericardial space. In the example ofFIGS. 7 and 8, an expandable end 332 forms a design for facilitatingdirectional deployment of the selected treatment medium 14. Preferably,the electrode array 34 is carried on the expandable end 332, with theelectrode array 34 including a number of individual electrodes 35, allof which are connected to the link 38. As with the examples discussedabove, when a chemical or pharmaceutical agent is selected as thetreatment medium 14, the expandable end 332 may be connected via theconnector 32 to the treatment source 12 in order to form an infusionsystem 334 including a plurality of spaced infusion ports 336 which mayfunction to deliver chemical agents (drugs, alcohol, etc) to theexpandable end 332 and hence into the cardiac space. The expandable end332 may be expanded in a manner similar to that discussed above withrespect to the above-described Figures, using any suitable expansionmedium. In the example of FIG. 6 and in the example of FIGS. 7 and 8 thedelivery tip 330 includes a pair of expandable containing elements 338which, in accordance with the exemplary form shown, may function tocontain a chemical agent within a cardiac space. The containing elements338 may be formed from a variety of structures or materials, such as anexpandable metal such as NITINOL, foam, a balloon, or other structures.The containing elements 338 serve to contain the treatment medium 14within a selected space and also serve to prevent the treatment medium14 from migrating or leaking to other areas. The containing elements 338can be delivered in a collapsed state during catheter positioning andthen may be expanded before therapy, and may be constrained with asheath of desired. As a further alternative, there may be additionalcontaining elements 338 disposed at additional locations along thecatheter which can be positioned in any configuration. FIG. 6 shows aversion with proximal and distal containing elements 338 disposedproximally of the distally located electrodes. FIG. 7 shows spaced apartproximal and distal containing elements 338, with electrodes 35 andinfusion ports 336 disposed between the containing elements 338.Additionally, the example of FIGS. 7 and 8 includes a dorsal containingelement 339 which extends between the proximal and distal containingelements 338.

Referring now to FIGS. 9 and 10, another exemplary forms of a deliverytip 430 are shown and are assembled in accordance with the teachings ofa further disclosed example of the present invention. The delivery tip430 again is attached to or otherwise forms the distal end 26 of thedelivery assembly 22 and is shown protruding from the distal end 20 ofthe catheter 16. The delivery tip 430 in each of FIGS. 9 and 10 includeexpandable ends 432 which carry the electrodes 35. As outlined above,the electrode array 34 and the individual electrodes 35 are coupled tothe link 38, and may form a portion of the mapping system 37. If energyis selected as the treatment medium, the electrodes/electrode array alsoacts to deliver the treatment medium in the form of electrical energy.In each of the example shown, the electrodes 35 are oriented on longwire strands, which may take the form of an expanding fan shape (FIG. 9)or along a more rectilinear frame or array (FIG. 10). In the example ofFIG. 9, the strands are constructed of multiple independent wires whichcan be pushed into the cardiac space and then positioned to deliverenergy as the treatment medium. FIG. 10 shows a version with electrodesmounted on an expandable frame which can be placed in the cardiac space.These constructions could also be combined with, for example, theconstruction of FIGS. 6-8 to concurrently deliver an agent along withthe energy.

FIG. 11 illustrates the delivery of two of the above-describedembodiments at different locations into the pericardial space. Theenlarged fragmentary cross-section of the heart shows the pericardium A,the myocardium B, and the pericardial space C between the pericardium Aand the myocardium B. It will be understood that autonomic nervoustissue such as cardiac ganglia will reside in the pericardial space C.The top portion of FIG. 11 shows the delivery tip 130 of FIGS. 2 and 3delivered into the pericardial space C via an entry point D. Theexpandable end 132, when expanded, would fill a portion of thepericardial space C. Specifically, the expandable end 132 would expandto extend between the myocardium B and the pericardium A, and also wouldexpand along the pericardial space in a direction perpendicular to theplane of the drawing. Consequently, the electrode array 34 spreads outto occupy a greater space, as does the fluid retention element 136.

Similarly, the bottom portion of FIG. 11 shows a delivery tip which maybe the delivery tip 330 of FIG. 6 delivered into the pericardial space Cvia another entry point E. The containing elements 338 are expanded onopposite sides of the pericardium in order to effectively seal the entrypoint E. The infusion ports 336 of the infusion system 334 are disposedinside the pericardial space C in order to deliver the treatment medium14 as a liquid agent. The electrodes 35 of the electrode array 34 arealso disposed in the pericardial space C.

FIG. 12 illustrates the delivery of the catheter 16 to various locationsalong the heart. In the exemplary deployment of FIG. 12, the catheter 16is positioned along the transverse sinus of the pericardial space andthen navigated along the trunks of the superior vena cava, the aorta,and the pulmonary arteries. This exemplary positioning disposes thecatheter 16 adjacent multiple clusters of ganglia, each of which canthen be modulated by the electrodes 35 of the mapping system 34, andeach of which can then be subjected to treatment using any one or moreof the exemplary delivery tips described herein to deliver any one ofthe possible treatment mediums described herein Further, in the exampleof FIG. 12, the electrodes 35 are positioned at various locations alongthe catheter labeled F1, F2, and F3. Such a positioning may enable thecreation of a bipolar energy delivery field to facilitate broad areacoverage at each of the locations F1-F3.

FIG. 13 shows another exemplary delivery tip 530 assembled in accordancewith the teachings of another disclosed example of the presentinvention. The delivery tip 530 is shown coupled to the treatment source12 in the form of a reservoir for holding a liquid treatment medium. Thedelivery tip 530 includes a fluid infusion system 534 having a pluralityof spaced apart infusion ports 536 for delivering any one of theselected treatment mediums described herein from the reservoir via thelink 32 in the form of a suitable conduit. The delivery tip 530 alsoincludes containing elements 538 to seal the pericardial space C, andfurther includes a plurality of suction or evacuation ports 537 toselectively withdraw the treatment medium via a suitable return conduit539. In the example of FIG. 13, the infusion catheter 16 is placed intothe pericardial space C and attached to a suitable infusion pump/controlsystem 548 which preferably may be implanted anywhere in the body (e.g.subclavian, subdermal, abdominal cavity, etc.). One or more sensors 540can be placed along the body of the catheter/delivery tip, in thepericardial space C, on the surface of the heart, within the myocardium,or on the surface of the body. In some preferred forms, communicationbetween the sensors 540 and the control may be accomplished via wirelesstransmission. The sensors 540 determine if a cardiac event is occurring(arrhythmia, infarction, etc), and then communicate to the pump/controlunit to deliver an agent into the pericardial space C via the infusioncatheter.

FIG. 14 shows another exemplary form for a delivery tip 630 assembled inaccordance with the teachings of an additional disclosed embodiment. Inthe specific application illustrated, the catheter/delivery system ispositioned to modulate nerve tissue along the ventricles of the heartwithin the pericardial space C. The catheter 16 may be positioned toencircle the epicardial surface of the ventricles, and then may modulatethe adjacent nerve tissue. The delivery tip 630 includes a plurality ofthe electrodes 35 spaced along a length of the tip, and further includesan infusion system 634 having a plurality of spaced apart infusion ports636. The modulation can be by infusion of an agent and/or delivery ofenergy via the electrodes 35 along the catheter 16. The catheter can beoriented and aligned such that the infusion ports are positioned todeliver the agent at the top of the ventricles and allow the agent toseep down over the surface of the ventricles.

FIGS. 15-18 show several additional delivery tips assembled inaccordance with further teachings of the disclosed invention. Each ofthe examples of FIGS. 15-18 illustrate various forms of a cryogenicdelivery tip 730 for delivering thermal energy to selected nerve tissue.FIG. 15 shows the cryogenic delivery tip catheter with a cryogenicelement 732 positioned opposite a series of spaced electrodes 35, againfor mapping, navigation, and orientation as outlined elsewhere herein,and can be utilized by the operator to orient the catheter 16 with thecryogenic element 732 against myocardium. The delivery tip 730preferably includes an covering/coating 734 formed of a suitableinsulating material. The insulation prevents thermal energy fromdamaging or affecting other tissues.

FIG. 16 illustrate a slight variation on the delivery tip 730, as thecryogenic element 732 is carried by an expandable element 733. Theexpandable element 733 may be made the same as any of the otherexpandable elements discussed herein, and may be expanded using any ofthe exemplary expansion mediums discussed herein. In the example shown,the catheter 16 can be delivered with the cryogenic element/expandableelement in a collapsed state, and then the expandable element can beexpanded to provide broad surface coverage of the cryogenic element overmyocardium. The expandable element can have a relatively flatcross-sectional shape to facilitate placement in the pericardial space.Finally, FIG. 18 shows the cryogenic element 732 having an elongatedconfiguration with a corresponding larger elongate surface area.Electrodes 35 are spaced apart along the delivery tip. This version maybe particularly useful for cooling the ventricle.

In further accordance with one or more preferred forms of the invention,there may be certain methods and functionalities that may be, dependingon the specific form of implementation, common across the variousdevices and methods discussed herein. For example, it is preferable toimplement a system in which it is possible to navigate within thepericardial space to a targeted treatment area, identify the area to betreated, and to assess the effectiveness both during the procedure andafter the procedure. These methods may include, for example, ultrasoundvisualization, electrical-mapping, and filtering of electrical signalsdetected by, for example, the mapping array discussed herein. Suchsystems may enable one to visualize and detect ganglia, treat theganglia, and then assess the status of the ganglia. The status mayinclude whether the has been stunned, killed, or not killed. Such anassessment allows for a sub-acute treatment in which therapy is providedover a course of days, one or more periodic assessments are performed,and then the therapy may be made permanent if the assessment indicatesthat the therapy has the desired effect. In general, the systems andmethod outlined herein may allow treatment of the ANS while notaffecting the myocardium.

In one or more of the exemplary devices and methods discussed hereinthere are a number of exemplary ways to monitor autonomics duringtherapy, in preparation for therapy, or after therapy. For example, useof the electrodes or electrode array, which may include closely spacedbipole electrodes, coupled with the use of an algorithm to filter outfar-field signals of certain frequencies. One possible exemplaryalgorithm may be based on using the derivative of the electrogramvoltage itself. Preferably, the system may be able to pick up thesignals while excluding the cardiac myocyte related signals. Anadditional concept would be to use dynamic recordings; (i.e. an operatorcould use subthreshold stimulation or rapid stimulation and then use theeffects on the recorded electrograms to better define what theautonomics are). Further, a pressure sensor or a piezoelectric crystalwill help detect myocardial contraction when we are stimulating andwhichever contraction signal correlates with an electrogram whencaptured would allow exclusion of that particular electrogram sincecapturing that leads to muscle capture and thus is likely myocytegenerated. Finally, looking at effects on cardiac rhythm or functioncould also be used; i.e. non-excitatory impulses placed at the site ofrecording a particular type of signal that would result innoncapture-electrophysiology results (change in refractory period,contractility, inducibility of arrhythmia etc.) would be used to allowdeducing that these signals are in fact autonomic nerves.

In accordance with one or more preferred aspects, it may be desirable tospecifically identify the signals targeted for manipulation andsubsequent modulation. One goal is to identify electrograms arising fromthe cardiac autonomic system, retroatrial ganglia, and relatedstructures, and distinguish these electrograms from those arising fromthe atrial, ventricular, and related myocardium.

One aspect of this distinguishing algorithm looks at the frequency ofsignals. For example, if the frequency of the recorded signal is greaterthan 50 Hz these are unlikely to be originating from myocardium.However, these signals even when above this frequency cut off aredetected may be by themselves misleading since overlapping cardiacstructures may be giving rise to the impression of frequently firingmyocardial cells. Thus further aspects of this disclosure may clarifywhen high frequency signals do indeed represent neuronal ganglia orrelated structure activity.

One of the ways proposed to make this distinction involves templatematching of the electrogram morphology. The 50 Hz (or similar value) cutoff will apply only if there is a greater than 80% (or similar value)match in morphology of the electrograms being counted for frequencydetermination. Thus using this refinement of the filtering algorithmoverlapping structures which may be detected as rapid firing but willhave minimal similarity in electrogram morphology will be excluded.

To further refine the accurate detection of these electrograms involvesa dynamic algorithm where rapid stimulation at frequency in two ranges,one where myocardial capture is expected to occur at leastintermittently and a second where myocardial capture is unlikely tooccur. The recorded electrograms are compared pre and post burststimulation at the above two frequencies. The disappearance of one setof signals at relatively lower frequencies suggests that those signalswere myocardial in origin and the failure for lower frequencystimulation to effect another group of signals which then are decreasedor disappear at higher rate stimulation would be diagnostic of anon-cardiac (neuronal) origin for those signals. The now identifiedmyocardial signals are specifically filtered based on their electrogramcharacteristics and retained in the devices memory. Following the“intervention” (ablation, stimulation, blocking, alcohol, etc., or anyof the treatment means outlined herein) are reacquired to assessefficacy of the intervention.

Additional monitoring of autonomics could be accomplished through theuse of veratrum alkaloids to monitor for modulation and/or ablationefficacy. Veratrum causes bradycardia and hypotension, and these couldbe used as endpoints during modulation and/or ablation, whether theablation or means of ablation is energy-based (RF, AC, DC, etc.) orchemical based (alcohol, etc.), and to determine when treatment has beensuccessful. For example, Veratrum can be given, the modulation/ablationprocedure can be started, and then the modulation/ablation is continueduntil the bradycardia and hypotension is no longer detected.

An alternative agent to use to create the aforementioned endpoints andthat can be used as surrogates to monitor for treatment efficacy isOuabain. Ouabain applied to the epicardial surface (infused into thepericardial space) causes bradycardia and hypotension. Once again, amodulation/ablation procedure (energy based—RF, DC, etc or chemicalbased—alcohol, etc) can be performed after Ouabain administration andcontinue until the hypotension and bradycardia disappear.

The identification of ganglia and the navigation to selected ganglia maybe accomplished by sensing the ganglia signals, amplifying the gangliasignals, and then filtering out the myocardial electrograms. This may beaccomplished in at least one of three exemplary manners. First, avery-low noise amplifier could be used with, for example, a 10 KHzbandwidth. This arrangement could act as a front-end to pick up signalsfrom inside the heart, over the ganglia plexi. A high frequency,high-pass filter could be used in order to minimize the effect of motionand in order to filter out and/or ignore intra-cardiac electrograms(which would saturate the high-gain amplifier).

Second, near-field and far-field signals may be compared. In accordancewith this concept, if the near-field signal profile is very similar tothe far-field signal profile, then the delivery device is probablydisposed in muscle, such as the myocardium. However, if the differencesbetween the near-field signal profile and the far-field signal profileis distinctly different and surpasses a threshold, then the deliverydevice is probably disposed in nervous tissue, since far-field signalprofile will be weighted towards the abundant musculature. Accordingly,it would be desirable to have a narrow-to-wide variable tip recordingsystem. In such an implementation, the closely spaced bipoles would becompared to the more widely spaced bipoles, with morphology/templatematching to distinguish nerve from muscle.

Next, a catheter-based imaging system may be employed, which may includethermal spectral imaging, either alone or in combination withelectrograms. This may serve to distinguish the autonomics fromunderlying myocardium. A lower thermal profile with rapid electrograms,even with overlying atrial fibrillation, could help distinguish thesestructures.

In further accordance with one or more exemplary forms disclosed herein,it may be desirable to use radiopaque and/or echogenic coatings on thecatheter in order to assist visualization during the preparation andperformance of the treatment procedure. These or other sensingcomponents or methods may be used with treatment of chronic conditionsin order to sense, actuate, and treat such conditions. Such sensors maybe direct, in which the electrode or electrode array is disposed withinthe pericardial space, on the myocardium, or on the epicardium. Suchsensors also may be indirect, in which the sensor may be worn externallyon the skin.

In many applications, it may be desirable to stimulate or block nervesignals using a low current density so as not to capture cardiac muscle.The stimulation may be performed during diastole (when cardiac muscle isnot contracting and is not electrically as active).

When performing one or more of the methods outlined herein, it may bedesirable to leave the catheter or other device in place in thetransverse or oblique sinus. Consequently, there it may be desirable toanchor the catheter and/or the device in place in order to prevent thedevice from migrating to the ventricle or otherwise migrating out of thedesired treatment area. Exemplary forms of anchoring the device mayinclude, for example, mechanical means such as screws, barbs, orballoons, polymers such as clues or gels, or energy means such as RFwelding to attachments to tissues such as the epicardial surface of theheart or to the pericardial sac.

Those of skill in the art will understand that the modulation of thecardiac autonomics poses one or more are possible challenges. Thesepotential challenges include recording autonomic activity (fornavigation to the autonomics and for feedback of therapeutic efficacy.It is understood that the autonomics may be a number of autonomics whichare disposed in number of locations which may be dispersed across arelatively wide area, and which may need to be modulated simultaneouslyor nearly simultaneously. The autonomic preferably are modulated withoutdamaging, activating, or otherwise affecting the myocardium or otherstructures such as the aorta, the esophagus, the vagus nerve, etc.

The methods and devices outlined herein may offer a number of generalsolutions to one or more of the foregoing challenges and concerns. Thedevices and methods disclosed herein contemplate a number of differentmeans or mechanisms as well as approaches to recording the autonomicactivity as discussed above with respect to how to navigate, identifyand assess autonomic activity at a selected location. Additionally, theuse of chemical and/or pharmaceutical infusion into various spaces inthe pericardial sac, such as the oblique sinus, the transverse sinus,the aortocaval sinus, or the entire pericardial space, etc, may enablecoverage the very broad area which exceeds the actual area of theinserted device. Further, the use of devices or delivery tips withexpandable elements such as expandable metal materials such as NITINOL,a mesh material, an expandable balloon, or other expandable structures,enables the device to carry electrodes and/or agents (via sponges, foam,etc) to a relatively large areas (see, for example, FIGS. 2-10).Finally, the use of modulation in accordance with the teachingsdiscussed herein means that it is possible to affect nervous tissue(autonomics) without affecting the myocardium. This may be accomplishedusing, for example, low energy/frequency RF or DC modulation/ablation,vibration energy selective for autonomics, as well as chemical,pharmaceutical or other agents.

Electrical Energy for Mapping, Sensing, Modulation and/or Ablation

In further accordance with one or more exemplary forms outlined herein,modulation/ablation may be accomplished through the use of AC or DCelectrical energy to block nerve signals, stimulate nerve signals, orablate nerve tissue. Signals from autonomic ganglia may be blocked bypositioning electrodes or an array of electrodes in selected pericardialspaces such as the oblique sinus, the transverse sinus, or otherpericardial spaces). The electrodes can be mounted on any one of theexpandable element discussed herein to provide broad or dispersedcoverage. It is also contemplated to use saline or other fluid to act asa virtual electrode in order to again provide broad or dispersedcoverage, and to use containing elements of the type outlined herein inorder to seal a given space to contain the treatment fluid.

When electrical energy is selected as the treatment medium theelectrodes could provide high frequency AC signals to modulate,down-regulate or block signals on nerves or within ganglia. Further, thesystem may provide pulsed electric fields (PEF) to destroy nerve tissue(see U.S. Published Patent Application No. 20070265687). Direct current(DC) may be useful to selectively inactivate or destroy myelin and/ornonmyelinated nerves. The energy required to block/ablate is preferablychosen so as not to damage or modulate the myocardium.

Further, when electrical energy is selected as the treatment medium, theelectrodes could provide high frequency AC signals to modulate,down-regulate or block signals on nerves or within ganglia; further, itcould provide pulsed electric fields (PEF) to destroy nerve tissue (seeU.S. Published Patent Application No. 20070265687). Direct current (DC)may be useful to selectively inactivate or destroy myelin and/ornon-myelinated nerves—Energy required to block/ablate nerve withoutdamaging or modulating myocardium.

The threshold for tissue destruction varies based on the type of tissueand its state of health. For example, nerve tissue has a differentthreshold for injury or ablation than cardiac muscle. Since ourapproaches involve modulation of tissue from the external surface theproximity itself of the nervous system related structures when comparedto muscle allows an increased likelihood that the nervous tissue will bemodified without necessarily resulting muscle damage. Further, certainenergy forms such as low coulomb direct current energy rarely causespermanent muscle damage but frequency may result in temporary orpermanent ablation of some types of peri-cardiac nerve tissue. Also foranother example, nerve tissue itself may have different thresholds forinjury. Myelinated fibers may be less susceptible to direct current orradiofrequency beams compared to non-myelinated fibers while thepropensity for damage or ablation when using a chemical agent such asalcohol yields opposite results (myelinated fibers more susceptible thannon-myelinated fibers). The assessment and deployment of energy deliveryor chemicals can therefore be done in a manner to target specific typesof tissue or within a group of tissue specific types of fibers dependingon the type of heart rhythm or other cardiac disturbance beingmodulated. Thus, although the same regional autonomic fibers may betargeted with therapy based on the threshold to injury the type ofenergy delivered, whether or not DC current or RF energy or chemicalsare used treatment can be individualized for rhythm disturbances versusdecreasing cardiac pain.

One or more of the devices outlined herein provide electrodes in directcontact with ganglia or ganglia bundles, such as by mounting theelectrodes one or more of the expandable elements discussed herein inorder to achieve broad or dispersed surface coverage, or by mounting theelectrodes in a dispersed array of independent wires such as is found inFIGS. 9 and 10. Further, the electrodes may effectively make in directcontact with the desired treatment area by exposing the electrodes to ahypertonic saline or other fluid delivered to the pericardial area, withthe electrodes communicating alternating current (AC) and/or directcurrent (DC), thus turning the fluid into a “virtual electrode” whicheffectively contacts the nerve tissue to block or ablate/denervate atissue (see any of the foregoing embodiments with infusion ports). Thefluid fills the selected space and thus carries the DC or otherelectrical current to the selected area to either activate, block, orablate nerve tissue/autonomics. This allows both broad field coverageand the ability to modulate nerve activity at a distance.

The electrodes or electrode arrays mentioned herein may be used tostimulate nerve tissue, or to stimulate receptors on cardiac tissue. Theelectrodes may be used to stimulate receptors on the atria, which whenstimulated increase the sinus rate, and thus electrodes cold be placedin this region to stimulate and to pace the heart. The stimulating orblocking electrodes specifically designed to have preferential effectson the nerve fibers emanating from the cardiac ganglia and eitherinserting into the heart muscle or fibers that emanated from the heartmuscle and will traverse one of the ganglias. However, these electrodesmay also be used to target for the desired effect the gangliathemselves, the ganglia and underlying heart muscles, or in someinstances unique transitional or receptor cells that form the interfacebetween the nerve fibers and the heart muscles. In some instances uniquetransitional or receptor cells form the interface between the nervefibers and the heart muscles.

The electrodes or electrode arrays mentioned herein may be used todown-regulate or block nerve tissue, or to modulate receptors on cardiactissue. The electrodes may be used either directly or via receptors onthe atria, which when blocked decrease the sinus rate, and thuselectrodes could be placed in this region to control or reduce heartrate.

A stimulation threshold could be determined as a level at which therewould be enough to activate ganglia, but not enough to activate themyocardium (either ventricular or atrial), and this approach wouldprevent the treatment from being proarrhythmic.

There may be a combination of electrical energy and a chemical agent tostun, block, or ablate autonomic tissue. This combination would allowfor the targeting of autonomic tissue or cardiac pain fibers (e.g.relatively low-power energy and relatively low concentration of agent)without damaging myocardium as the nervous tissue will be more sensitiveto these modulation means than will myocardium. Specific examples ofsuch approaches include the use of low energy AC/DC/RF combined withalcohol. It may be preferable to use alcohol as the irrigating mediumalong with AC, DC or RF, since it may be desirable to use a low enoughAc and/or DC energy level solely for neuro-blocking or electrolysis,along with the alcohol for a similar effect. By changing the relativeproportion of AC energy, DC energy, RF energy, and the alcoholirrigation could allow differential ablation of one specific componentof either the autonomic nerves or the cardiac pain fibers.

The disclosed catheter and deliver systems outlined herein may be usedto deliver energy or a chemical agent to stun, block, or ablateautonomics near the transverse sinus. Based on anatomy, it may beimportant in at least some applications to completely or nearlycompletely encircle the main pulmonary trunk, while still having acatheter seated in the transverse sinus. We thus envision acatheter/delivery assembly capable of placement within the transversesinus, which may also have a blunt tip that is deflectable andextendable from the main catheter body. The extendable tip will bepushed forward and will course between the SVC and the main pulmonaryartery trunk, lateral to the ascending aorta and circle anterior to themain pulmonary trunk. The catheter/delivery assembly may then clasp in alasso or ring-like conformation around the medial or leftward portion ofthe main pulmonary arteries (see FIG. 14). This design wouldspecifically be helpful for the sympathetic and other autonomic ganglialocated in proximity to the superior vena cava and around the pulmonarytrunk. This additional catheter/delivery assembly design could be anaddition to the primary dual surface transverse sinus catheter describedabove with the extendable element extended to go completely aroundeither or both of the great arterial trunks.

The delivery assembly may have multiple electrodes positioned along thelength of the delivery tip, such as is seen in many of the foregoingFigures, order to create a bipolar field over which energy could bedelivered between electrodes and thereby create a larger field in whichto stun or ablate nerve tissue within the field. The stimulatoryelectrodes may be mounted on the expandable element as shown in numerousof the foregoing embodiments, or mounted on multiple independent wiresas shown in FIGS. 9 and 10, and may be placed in the oblique sinus forhigh-rte stimulation of autonomic tone of the atria or in the region ofthe aorto-caval ganglion for atrial rate control and to treatventricular fibrillation.

Mechanical Energy for Mapping, Sensing, Modulation and/or Ablation

The present device and method also contemplates modulation/ablationusing mechanical energy. For example, the delivery assembly may use apiezoelectric element to perform one or more of a mapping function inorder to find the autonomics, to stun the autonomics at a selectedtreatment areas, to assess the result of treatment, and to usevibrational energy created by the element to ablate or kill localautonomic activity at the selected treatment area. Ablation may also beperformed using HIFU, AC or DC.

Other mechanical means may include the use of abrasion element or ablade device to perform a local neurectomy. The device may function tolocate and/or orient the treatment delivery tip assembly and thenmechanically disrupts the relevant tissue. Such a device may alsoinclude serrated/barbed edges, blades or other elements, which elementsmay be arranged to rotate against pericardial sac and/or against theepicardial wall of the atrium. Additionally, vibrational energy in theform of either piezoelectric vibration or mechanical vibration may beuseful in order to terminate ventricular and/or atrial fibrillation.

Chemical Agents for Modulation and/or Ablation

The present device and method also contemplates the use of chemicalagents for modulation, blocking, and/or ablation of autonomic nervesignaling. The delivery assembly may include a pump/reservoir system,which preferably utilizes the catheter, to deliver an agent into thepericardial space to block/stun, or kill/ablate nerve tissue. Exemplarydevices could be placed by the subxyphoid approach, and may include ananchoring/stabilizing expandable element (balloon, nitinol, etc., of theexemplary forms discussed above, to prevent the device from slippingback into the thoracic cavity (see FIGS. 6-8, 11 and 13) A chemicaldelivery device infuses an agent through a port or array of diffusionports, and could have additional ports for removing the agent and/orflushing the space with saline/water after the agent has been removed.

A supply source and/or a pump preferably is connected to the sensingarray or system, and if arrhythmia is detected the system can dispense asuitable chemical agent into pericardial space or to another targetedtreatment location. A suitable electrode sensor could be placed in thepericardial space, on the epicardial surface, within the myocardium, oron the skin to sense ECG signals or other signals to detect a cardiacdisorder (e.g. arrhythmia). The system may then activate the pump inorder to dispense the agent. Further, the could be dispensed from acatheter placed in any pericardial space (oblique sinus, transversesinus, pericardial sac, etc.). The agent could be any agent thattemporarily blocks nerve signaling such as, for example, Bupivocaine,lidocaine, a cooled fluid, procainamide, etc. The pump/reservoir couldbe located externally, or in the thoracic cavity, or subdermally (forease of refilling).

A system employing a chemical agent and an associated pump, etc., couldreadily be combined with other means (e.g. instill the agent, and thenuse mechanical, thermal, or electrical means to further enhancemodulation) In one exemplary embodiment, a selected space (pericardial,sinuses) could be instilled with saline which acts to carry RF, AC or DCenergy to a large area. The space could be filled with alcohol and thenenergy could be delivered using one or more of the above-mentionedmechanisms, such as RF, AC, DC, etc., or mechanical means.Alternatively, one of the above-described expandable devices could beused and could contain both a sponge/mesh for delivering agent and alsocontain electrodes for delivering energy (see FIGS. 2 and 3 forexample). Another contemplated version expands from a compressed statefor delivery through the catheter and then shifts to an expanded,deployed state upon exiting the catheter (e.g. nitinol mesh/framework,balloon, foam, etc). The expanded device would provide greater surfacearea coverage for modulating the tissue and also could conform to agiven space (e.g. oblique sinus or transverse sinus). The expandeddevice could contain or be covered by a sponge/fabric/foam which couldretain the agent to be delivered to contain the agent to a given area(i.e. prevent damaging surrounding tissues) and also keep the agent atthe area for a longer period of time (prevent the agent from beingwashed away).

The expanded device could contain or be covered with electrodes whichcould be used for mapping/orientation or for delivering energy tostun/kill/denervate nerve tissue. The catheter with an expandableelement (mesh, sponge, foam) carrying a drug combination to a givenpericardial space. In terms of specific drug combination, the use of afixed mixture of procainamide along with an alpha-blocker such asphentolamine or phenoxybenzamine along with a viscous gel and alcohol.This could be exuded through the pores of the sponge-like element and,which in turn, is temporarily inserted in the pericardial space, toassess efficacy for a few days and then the same catheter/element setused for more permanent ablation either by an injection of a greaterstrength of the same agents, different agents, or the combination ofagents and electrical energy (RF, AC or DC) using electrodes mounted onthe expandable element.

Pump/system could be used acutely (fill space with agent—treat—thenremove device) or chronically (implantable pump system to periodicallydeliver agent or deliver agent based on actuation by sensor component).Pump (catheter version) could have an expandable element(s) thatattaches to or protrudes from catheter (balloon/nitinol mesh/foam) whichexpand and can contain the delivered agent to a given space (see FIG.13). Pump (catheter version) could have means to provide orientation ofthe device within a given space. Orientation could be provided bydifferential coatings (e.g. one side of the catheter is coated with anechogenic or radiopaque coating that could be seen by ultrasound orx-ray respectively. Alternatively, orientation could be provided byelectrodes on the catheter or on a device that protrudes from thecatheter. (See FIG. 5).

For treatment in the Transverse Sinus, the catheter would be oriented toplace the electrodes in contact with myocardium. This would allow theoperator to receive an ECG signal from the myocardium and know that thecatheter is correctly oriented. The operator could then infuse an agentdirectionally to ablate, block autonomics on the pericardial sac (awayfrom the surface of the heart) (see FIGS. 6-8). For treatment in theOblique sinus, the catheter would be positioned opposite that of thetransverse sinus (i.e. electrodes against the pericardial sac such thatno ECG signals are seen). Catheter placed around the ventricles todeliver an agent and/or energy to block, stun, or ablate cardiac painfibers to treat chronic intractable chest pain (see FIG. 6). Apump/catheter could deliver agents to stun or temporarily block nerveactivity such as Trimethophan, Quinadine, Procanamide, Bupivocaine,Phenoxybenzamine, Phentolamine, Anticholinergics, Alpha and BetaBlockers, Hexamethonium, Pentolinium, Mecamylamine, Pempidine, and couldalso deliver agents to permanently ablate/destroy/block nerve activitysuch as Phenol, Ethanol, Ammonium Salts, Phenoxybenzamine, Formalin.

Specific electrodes designs are contemplated for alcohol±DC currentapplications. A sponge-like electrode made of, for example, non-nitionalcomponents that may be expanded and placed in the oblique sinus so thattrue small ports alcohol can be effused and the non-nitinol segmentswill absorb any leakage preventing and/or minimizing more widespreadeffects. The same course may have electrodes which permit placement ofRF current or DC current or electrolytic doses of DC current to producemaximal effects of the alcohol on the ganglia in positions of contact.

Thermal Modulation and/or Ablation

Thermal or radiofrequency means may be used to performmodulation/ablation. Ablation of receptors on the ventricle may be usedto increase the sinus rate, and thus the device may function as apacemaker. The ablation of subepicardial ventricular receptors may alsobe performed, as can RF ablation with saline as virtual electrode (SeeFIGS. 2-8. Cryogenic energy can be used to cool the epicardialsurface/pericardium of the heart (both autonomics and/or myocardium) toterminate arrhythmias. This could form the basis of painlessdefibrillation. Cooling could be accomplished by several means, such asthe injection of cooled fluid into pericardial space or into deviceplaced in contact with atria or ventricle or ganglia. A cooling of meshmay be brought into contact with the heart (e.g. by use of Peltier typesystem as outlined in U.S. Pat. No. 5,515,682). Chemicals which mix andcause an endothermic reaction could be used, as can cenergy totransiently block signaling/ablate nerve tissue. Cryogenic catheterswould be positioned as described above for placement in the transversesinus or oblique sinus. Transverse sinus, the cryogenic source would beoriented away from the epicardial surface of the heart, and towards theepicardial surface of the heart in the oblique sinus. Electrodes mountedon the cryogenic catheter could be used to orient the catheter correctly(See FIGS. 15-18). Operators may perform cryogenic cooling for atrialfibrillation (relatively slow cooling) with a device that protects theesophagus (see FIG. 18), which offers large surface covering and rapidcooling for ventricular fibrillation.

Cooled saline or other refrigerants may be used. In accordance with oneexemplary aspect, cooling can be used as part of an implanted systemwhich is left in the body using the type of sheath described above toprevent leakage. One contemplated method is an endothermic reaction thatwould occur on contact, and which may cause an immediate or nearimmediate and relatively sudden cooling. When this cooling occursarrhythmia may be suppressed both because of the effects of the coolingon the autonomics and perhaps due to the effects of cooling on theventricular myocardium itself. This approach would in fact be a type ofcryo manipulation. In addition, a contemplated approach envisions thiscooling can be done temporarily and regionally, i.e., not for the wholeheart but at specific chosen locations, such as the ganglia behind theatrium.

Modulation of the cardiac autonomics, interventricular myocardium, orthe receptors/transitional regions between nerve fiber and myocardiummay be used for non-arrhythmia indications. These include control ofcardiac chest pain, modulation of cardiac activity and contractions, orin some instances to increase the heart rate. In some cardiac conditionssuch as neurocardiogenic syncope there is over activity of some of themechanoreceptors that modulate a reflex designed to prevent overvigorous cardiac contractions. An untoward effect of activities fromthese receptors is inordinate lowering of the blood pressure or slowingof the heart rate. The methods described may be used to target thesereceptors or the nerves that originate in these receptors where by theabnormally low heart rate may be modulated to increase potentiallyobviating the need for a pacemaker in some instances. On the other hand,these same receptors may also be dysfunctional and create abnormallyhigh heart rates and blood pressure and either stimulation blocking orablation of these receptors may be helpful in reducing theseabnormalities as well.

In accordance with one or more of the aspects outlined herein, treatmentmethods and treatment devices may be viewed in modular form. Thesemodules include options for accessing the relevant space or treatmentare, options for mapping and/or identifying the ganglia or autonomicnervous system activity, options for modulating the ganglia of otherautonomics, and options for interpreting and/or assessing the results ofthe modulation.

For example, the options for accessing and/or covering the desired orselected treatment area include accessing any one or more of thepericardial space (e.g. subxyphoid access, thoracotomy), the epicardialsurface, the oblique sinus, the transverse sinus, retro-atrial area, orbroad field coverage (cover a relatively large area to get all gangliaor broad ganglia coverage, which can be spread out over a relativelylarge area).

The options for mapping and/or identifying the ganglia activity or otherautonomic nervous system activity include the algorithms and filteringdiscussed above regarding various aspects of distinguishing and/ormatching electrogram morphology. Further options exist, such as may befound in Feasibility Study of Endocardial Mapping of GanglionatedPlexuses During Catheter Ablation of Atrial Fibrillation, Lemery et al.,Heart Rhythm Society, (1996); Combined Effect of Pulmonary VeinIsolation and Ablation of Cardiac Autonomic Nerves for AtrialFibrillation, Ohkubo et el., (2008); and in Gross and MicroscopicAnatomy of the Human Intrinsic Cardiac Nervous System, Armour et al.,The Anatomical Record, 247:289-298 (1997).

Further, the various mechanisms or means for modulating and/or ablatingnervous system activity may be selected from any one of the foregoingmechanisms or means. For example, one may choose electrical means, suchas, for example, alternating or direct current energy, for stimulationand blocking of activity. Mechanical options also may be chosen such as,for example, ultrasound, vibration, or other physical disruption orapplication of kinetic energy. Chemical means may be chosen from any oneof the foregoing discussed examples, and thermal means may be chosen,again from any one of the foregoing discussed examples, includingheating, cooling, cryogenic and/or RF energy.

Finally, the options for assessing and/or interpreting the results ofthe modulation include mapping of the relevant nervous system orautonomic activity after the treatment step. These options would alsoinclude assessing and/or interpreting indirect results of the modulationstep such as, for example, surrogate biological functions includingheart rate, blood pressure, etc.

Is used herein, autonomic activity and/or autonomic regulation may beused to refer to any of the ganglia activity or nervous system activitydiscussed herein. Therefore, it may be convenient to use the termautonomics to apply generically to these various types of activity.These specific types of activity are mentioned for explanatory purposesonly, and are not intended to limit in any way the scope of the claimsappended hereto.

Numerous modifications and alternative embodiments of the invention willbe apparent to those skilled in the art in view of the forgoingdescription. Accordingly, this description is to be construed asillustrative only and is for the purpose of teaching those skilled inthe art the best mode of carrying out the invention. The details of thepresent disclosure may be varied without departing from the spirit ofthe invention, and the exclusive use of all modifications which arewithin the scope of the claims is reserved.

1. A method of modulating the autonomic nervous system adjacent apericardial space to treat cardiac disorders comprising the steps of:providing a source of a treatment medium, the treatment medium effectiveto ablate autonomic nervous system activity; providing a catheter havinga proximal end and a distal end, the distal end sized for insertion intothe pericardial space at an entry point; providing a delivery assemblyfor delivery of the treatment medium, the delivery assembly having aproximal end and a distal end, the distal end arranged to be positionedby the distal end of the catheter; providing the distal end of thedelivery assembly with a delivery tip and a mapping array, the deliverytip operatively coupled to the source and arranged to deliver thetreatment medium, the mapping array arranged to sense a level ofautonomic nervous system activity within the pericardial space and tocreate an output; using the output to position the delivery tip at aselected treatment location within the pericardial space; and performinga modulation step by supplying the treatment medium to the selectedlocation via the delivery tip.
 2. The method of claim 1, including:providing the delivery tip of the medium delivery assembly with aplurality of delivery points; and using the plurality of delivery pointsto disperse the treatment medium at a plurality of treatment areaswithin the pericardial space.
 3. The method of claim 1, including:providing the delivery tip of the medium delivery assembly with adispersion means having an exposed area; and using the dispersion meansto disperse the treatment medium over a treatment area, the treatmentarea greater than the exposed area.
 4. The method of claim 1, including:using the mapping array after the modulation step to sense a follow-uplevel of autonomic nervous system activity at the selected location; andcomparing the follow-up level of autonomic nervous system activity to athreshold.
 5. The method of claim 4, including: determining whether thefollow-up level of autonomic nervous system activity is above athreshold; and performing a subsequent modulation step.
 6. The method ofclaim 1, including: providing a monitor arranged to create an output;periodically using the mapping array after the modulation step to sensea follow-up level of autonomic nervous system activity at the selectedlocation and providing a subsequent output to the monitor; comparing thesubsequent output to the threshold level of autonomic nervous systemactivity; and determining whether an additional modulation step isdesired.
 7. The method of claim 1, including: providing a monitorarranged to create an output; using the mapping array after themodulation step to sense a follow-up level of autonomic nervous systemactivity at the selected location and providing a subsequent output tothe monitor; comparing the subsequent output to the threshold level ofautonomic nervous system activity; determining whether an ablation stepis desired; and performing the ablation step by supplying the treatmentmedium to the selected location via the delivery tip.
 8. The method ofclaim 7, including: determining an amount of the treatment mediumeffective to perform the ablation step.
 9. The method of claim 1,including: determining a desired duration for the modulation step; andperforming the modulation step for the desired duration.
 10. The methodof claim 1, including: using the mapping array after the modulation stepto sense a follow-up level of autonomic nervous system activity at theselected location; comparing the follow-up level of autonomic nervoussystem activity to a threshold; performing a subsequent permanentmodulation step.
 11. The method of claim 1, further including: providingthe delivery tip with an expandable portion shiftable between acollapsed state and an expanded state; coupling the delivery tip to theexpandable portion; expanding the expandable portion after placement ofthe delivery tip at the location within the pericardial space.
 12. Themethod of claim 1, including: selecting the treatment medium as one ofelectrical energy, a pharmaceutical composition, a chemical composition,an exothermic agent, an endothermic agent, or vibration.
 13. A method ofmodulating the autonomic nervous system adjacent a pericardial space totreat cardiac disorders comprising the steps of: providing a source of atreatment medium, the treatment medium effective to modulate or ablateautonomic nervous system activity; providing a catheter having aproximal end and a distal end, the distal end sized for insertion intothe pericardial space at an entry point; providing a delivery assemblyfor delivery of the treatment medium, the delivery assembly having aproximal end and a distal end, the distal end arranged to be positionedby the distal end of the catheter; providing the distal end of thedelivery assembly with a delivery tip, the delivery tip operativelycoupled to the source and arranged to deliver the treatment medium;using a sensing means to position the delivery tip at a selectedtreatment location within the pericardial space; and performing amodulation step by supplying the treatment medium to the selectedlocation via the delivery tip.
 14. A method of modulating the autonomicnervous system adjacent a pericardial space to treat cardiac disorderscomprising the steps of: providing a catheter having a proximal end anda distal end, the distal end sized for insertion into the pericardialspace; providing a delivery assembly, the delivery assembly having aproximal end and a distal end, the distal end arranged to be positionedby the distal end of the catheter; providing the distal end of thedelivery assembly with a delivery tip, and providing the delivery tipwith an electrode array; positioning to the catheter to place thedelivery tip at a location in the pericardial space; using the electrodearray to take a first indication of autonomic nervous system activity atthe location; using the electrode array to apply electrical energy atthe location; using the electrode array to take a second indication ofautonomic nervous system activity at the location; and comparing thefirst indication and the second indication to determine whether theautonomic nervous system activity has been modulated at the location.15. The method of claim 14, further including: providing the deliverytip with an expandable portion shiftable between a collapsed state andan expanded state; positioning the electrode array on the expandableportion; expanding the expandable portion after placement of thedelivery tip at the location within the pericardial space.
 16. Themethod of claim 15, including forming the expandable portion from anexpandable metal material; securing the expandable portion in thecollapsed state using a sheath; shifting the expandable portion to thedeployed state by removing the sheath after placing the expandableportion at the location.
 17. The method of claim 15, including formingthe expandable portion from a balloon; coupling the balloon to anexpansion medium; shifting the balloon to the deployed state bycommunicating the expansion medium to the balloon after placing theballoon at the location.
 18. The method of claim 14, including:providing a processor operable to execute a filtering algorithm;providing an electrical coupling between the electrode array and theprocessor; communicating the first indication to the processor as afirst input and the second indication to the processor as a secondinput; using the filtering algorithm to generate to an output indicativeof the first indication or the second indication; and comparing theoutput to a threshold level of autonomic nervous system activity. 19-50.(canceled)